| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Science to Practice |
Department of Radiology
Beth Israel Deaconess Medical Center
1 Deaconess Rd
Boston MA 02215
jkruskal@bidmc.harvard.edu
SUMMARY
McCarville et al have used gray-scale contrast-enhanced low-mechanical-index, and thus non–bubble-destructive, continuous US to quantitate tumor blood flow in mouse tumors engineered to simulate antiangiogenic therapy. They have shown that contrast-enhanced gray-scale US, unlike power or color Doppler US performed without contrast enhancement, is better able to depict and distinguish microvascular flow in subcutaneously implanted mouse tumors possessing different vascular phenotypes.
THE SETTING
The widespread clinical introduction of antiangiogenic therapies for the treatment of patients with solid malignancies has stimulated an active and necessary search to identify imaging correlates for quantitating response to these agents. While the molecular mechanisms of action of many of these agents are known, the precise in vivo microvessel and flow alterations produced by many of these antiangiogenic agents remain unclear. Furthermore, the recognition that tumor neovasculature might transform to a mature phenotype during treatment with some antiangiogenic therapies (1), coupled with the fact that agents may target mature and/or immature blood vessels in tumors and cause different degrees of regression (1), emphasizes the need for development of sensitive noninvasive indexes of the kinetics of tumor blood flow and perfusion. Accordingly, efforts to quantitate tumor perfusion by applying a variety of indirect kinetic parameters to data acquired by using computed tomography (CT), magnetic resonance (MR) imaging, or ultrasonography (US) have resulted. Early research efforts, using mainly CT and MR imaging, focused on identifying imaging correlates of histologic reference standards—namely, the microvessel densities (2).
|
THE SCIENCE
McCarville et al (3) employed mouse models in which tumor cells followed one of two abnormal pathways of angiogenesis. Neuroblastoma cell lines were engineered to continuously overexpress one of two angiogenesis inhibitors, which differed in their mechanisms of inhibition. First, cells producing truncated soluble fetal liver kinase-1, a decoy receptor for vascular endothelial growth factor, inhibit activation and thus migration of endothelial cells to result in a reduction in the absolute number of endothelial cells present in a growing tumor (4). Tumor perfusion in this model thus reflects regressive changes in established tumor vessels that occur with antiangiogenic therapies. Second, cells expressing tissue inhibitor of matrix metalloproteinase-3 prevent immature vessels from maturing by inhibiting the pericyte migration and activation required for vessel stabilization; this model thus reflects antiangiogenic drugs targeting developing or immature vessels present during initial stages of angiogenesis. The mouse model therefore allowed the investigators to evaluate changes in tumor perfusion caused by different mechanisms simulating the clinical setting of two entirely different antiangiogenic drugs.
The use of contrast-enhanced low-mechanical-index (thus, non–bubble-destructive) US by McCarville et al (3) allows circulating bubbles to remain intact and permits real-time acquisition of blood flow and tumor perfusion indexes. The authors were therefore able to distinguish experimental tumors from control tumors by means of the lower rates (change in signal intensity from baseline to initial peak) and extent of initial contrast agent inflow (rates of increase in signal intensity). The rates of contrast agent inflow also were strongly associated with immunohistochemical markers of vascular density. What would also be important to document is whether any of the indexes measured was able to help distinguish between the two engineered tumors. Color and power Doppler US without contrast enhancement were unable to be used to assess tumor vascularity in the control and treated tumors that were studied.
THE PRACTICE
Clinical use:
More options now exist for the imaging evaluation of patients undergoing antiangiogenic therapies. Nondestructive real-time gray-scale US permits continuous monitoring of different indexes of tumor blood flow and deserves to receive full and fair evaluation in comparative clinical trials. While being relatively noninvasive and devoid of the risks associated with radiation exposure, US will need to compete with CT and MR imaging for this expanding and important clinical niche.
Future opportunities and challenges:
Newer US technologies now exist for further enhancing low signal arising from tumor microvessels. For example, the introduction of power pulse inversion and contrast pulse sequence imaging software permits continuous real-time imaging of perfusion at a low mechanical index. Opportunities clearly exist for studying and comparing the ability of these US technologies to help distinguish between different pathways of tumor vessel regression and can be compared with the complex mechanisms of action of the different antiangiogenic agents.
Other technical and software advances are anticipated for improving microvessel detection and characterization of low-velocity flow in tumors. As an example, simultaneous display of low-velocity perfusion and higher-velocity vascular flow has been described with use of combined radiofrequency and Doppler filtering (5). In addition, by binding endothelial-specific monoclonal antibodies (6) or tumor-specific peptides (7) to the surface of microbubbles, specific vascular beds can be targeted for improved sonographic characterization of tumor microvasculature. It is important to compare the relative sensitivities and specificities of MR imaging, CT, and US to document which imaging technology is best for these purposes.
FOOTNOTES
See also the article by McCarville et al in this issue.
References
Related Article
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| RADIOLOGY | RADIOGRAPHICS | RSNA JOURNALS ONLINE |
